Anti-metabolite nucleosides and nucleoside analogues have found widespread use in the treatment of cancer and other human diseases. 6-mercaptopurine was found by Elion and co-workers to infer with purine metabolism and is used in the treatment of leukemia. Other nucleosides or nucleosides analogues that are of use include trifluorothymidine, arabinosyl cytidine.
5-Fluorouracil (5-FU) has been used continuously since its development in 1957 by Duusinski and Heidelberger (U.S. Pat. No. 2,802,005) for the treatment of solid tumors of the head, neck, breast, and colon. 5-FU was originally designed to work as an inhibitor of thymidylate synthetase (TS). TS is the enzyme which converts deoxyuridine 5'-O-monophosphate (dUMP) to deoxythymidine 5'-O-monophosphate (dTMP). It is believed that 5-FU retards tumor expansion by causing thymidine pools to become depleted in rapidly proliferating tumor cells.
Protocols for the administration of 5-FU for treatment of human cancer involve infusion of the drug for long periods of time. 5-FU is rapidly metabolized and excreted with a half-life in-vivo of about 18 minutes. While 5-FU is an effective anti-cancer agent when metabolically activated to become an inhibitor of TS its effectiveness is hampered by rapid metabolism and formation of 2-fluoro-.beta.-alanine (FBAL) which is neurotoxic and cardiotoxic. For these reasons researchers and clinicians have long desired a method of increasing the therapeutic index and target specificity of 5-FU.
A variety of pro-drug forms of 5-FU have been developed to address the issues of cellular uptake, sustained release, organ distribution, and transdermal or intestinal uptake that are problematic for the native drug. One of the most widely studied pro-drug forms of 5-FU is 5'-deoxy-5-fluorouridine (DFUR). DFUR is converted to 5-FU by pyrimidine nucleoside phosphorylase but has better cellular uptake properties than 5-FU. Like 5-FU, DFUR also releases FBAL as a toxic metabolite. Other nucleoside analogues of FUr include Tegafur [(1-(2-tetrahydrofuryl)-5-fluorouracil], Ftorafur [R, S-1-(tetrahydro-2-furanyl)-5-fluorouracil] and a variety of 5-fluorocytidine derivatives.
A variety of polymeric forms of 5-fluorouridine have also been prepared to provide sustained release of 5-FU. 5-Fluorouracil has been prepared as a conjugate of chito-oligosaccharides and also as a conjugate of poly(ethylene glycol). These polymeric forms were designed to provide macromolecular drugs with reduced side-effects and strong anti-tumor activity and showed good biological activity and low toxicity in animal models. The chief advantages of FdU.sub.n and FrU.sub.n compared to other polymeric structures are that the oligonucleotide based oligomers are readily taken up by cells, perhaps through a facilitated mechanism. Also, enzymatic degradation of the oligomeric 5-fluorodeoxyuridine results directly in release of the fully activated inhibitor of thymidylate synthase (FdUMP). Oligonucleotide based polymers retain the advantages that make other polymers useful such as increased bioavailability. Homo-oligomeric compositions of other nucleoside antimetabolites benefit from positive increase in bioavailability and cellular uptake. Homo-oligomeric anti-metabolite nucleotides are synthesized and used as a polymeric drug delivery system.